Adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life. Leukocyte trafficking, recruitment to sites of inflammation, tumor cell adhesion to endothelial cells and metastasis are mediated by three adhesion receptor families, the integrin and immunoglobulin superfamilies and the recently described selectin family. The known selectins contain an N-terminal lectin domain that mediates adhesion by binding carbohydrate ligands on opposing cells. The lectin domain is followed by an epidermal growth factor-like domain and a series of consensus repeats similar to those found in complement regulatory proteins. The selectins are expressed on activated endothelial cells and platelets and are implicated in the recruitment of neutrophils and monocytes to sites of tissue injury.
E-selectin is a selectin that is transiently expressed on endothelial cells 2-8 hr after stimulation of IL-1 and other inflammatory agents, and mediates a neutrophil adhesion pathway distinct from that mediated by ICAMS and leukocyte integrins. The neutrophil chemoattractant IL-8, which is secreted by activated endothelial cells, acts on neutrophils as a feedback inhibitor to attenuate the hyperadhesive interaction between neutrophils and E-selectin receptors. P-selectin is located in .alpha.-granules of platelets and Weibel-Palade bodies of endothelial cells, and is rapidly mobilized to the surface of these cells after stimulation by products of the clotting cascade such as thrombin, where it mediates adhesion of neutrophils and monocytes. Selectins function in a wide range of cell interactions in the vasculature and are expressed both on leukocytes and endothelial cells. Selectins mediate adhesion events within the blood vascular compartment through calcium-dependent recognition of specific carbohydrates.
The acquisition of invasive properties by tumorigenic cells constitutes an essential step in tumor progression. Since most malignant tumors are carcinomas, the molecular mechanisms underlying the invasion of epithelial cells are of particular interest.
Over 90% of human tumors are carcinomas; in these, transformed epithelial cells grow in an uncontrolled fashion, break through the basement membrane, and invade the underlying mesenchyme. Local invasion can compromise the function of involved tissues. It has been shown that the state of differentiation and the concomitant degree of invasiveness of carcinomas can determine cancer progression. However, the most significant turning point in the disease is the establishment of metastasis. It is known that the malignant phenotype is the culmination of a series of genetic changes that involves both positive and negative regulatory elements. Investigation of the activation, regulation, mutation, or somatic deletion of genes that encode these regulatory elements presents a new frontier for research into the complex cellular interactions that precede the development of metastasis.
The morphological and functional characteristics of carcinomas were recognized years ago; the underlying molecular basis, however, is only presently accessible to the investigation on a molecular level. Thus, there is a great clinical need to elucidate the underlying molecular basis of cellular adhesion and its role in inflammatory responses and metastasis and to develop compounds that can modify these cellular interactions. The present invention satisfies this need and provides related advantages as well.